How BRCA1/2 mutations cause cancer?

More than 20 years after scientists revealed that mutations in the BRCA1 gene predispose women to breast cancer, scientists have pinpointed the molecular mechanism that allows those mutations to wreak their havoc.

The findings, reported in the journal Nature, will not only help researchers design drugs to combat breast and ovarian cancers, but also help identify women who are at high risk of developing them, the authors say.

"There have been about 14,000 papers written about BRCA1, and you would think we already know everything about the gene, but we don't," said senior author.

The discovery of BRCA1's role in DNA repair and suppression of tumors was the first evidence that the risk of cancer could be inherited. It was originally thought that mutations in BRCA1 and the related BRCA2 gene might account for 7% to 8% of breast and ovarian cancers, senior author said. However, the cancer risk is likely a lot higher because in many cancer cases the expression of the BRCA genes is silenced even though no mutation can be found, author added.

Researchers showed in their Nature paper that the interaction of BRCA1 with its partner BARD1 is necessary to recruit the exact genetic sequence needed to repair breaks in DNA caused by endogenous stress and environmental insults such as radiation exposure. Authors show that BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1–BARD1 enhances the recombinase activity of RAD51.

Mechanistically, BRCA1–BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. They also provide evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1–BARD1 mutants with weakened RAD51 interactions show compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells.

"Defining the mechanism of the BRCA-dependent DNA repair pathway will help scientists design drugs to kill cancer cells more efficiently," senior author said.

"Understanding this mechanism will provide the predictive power for doctors trying to establish a patient's personal risk of developing cancer."